Medical Policy

Policy Num:      11.003.081
Policy Name:    Genetic Testing for Macular Degeneration
Policy ID:          [11.003.081]  [Ac / B / M- / P-]  [2.04.103]

Last Review:       April 18, 2024
Next Review:       April 20, 2025
 

Related Policies: None

Genetic Testing for Macular Degeneration

Summary

Description

Age-related macular degeneration is a complex disease involving both genetic and environmental influences. Testing for variants at certain genetic loci has been proposed to predict the risk of developing advanced age-related macular degeneration. Age-related macular degeneration is divided into the dry form, associated with slowly progressive vision loss, and the wet form, which may be associated with rapidly progressive and severe vision loss. The risks of age-related macular degeneration and of developing the wet form are associated with genetic and nongenetic (eg, age, smoking) factors.

Summary of Evidence

For individuals who are asymptomatic with risk of developing age-related macular degeneration who receive genetic testing for age-related macular degeneration, the evidence includes genetic association studies and risk-prediction models. Relevant outcomes are test accuracy, change in disease status, and functional outcomes. The clinical validity of genetic testing appears to provide a small, incremental benefit to risk stratification based on nongenetic risk factors. The clinical utility of genetic testing for age-related macular degeneration is limited, in that there are currently no preventive measures that can be undertaken. No studies have shown improvements in health outcomes in patients identified as being at high-risk based on genetic testing. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with age-related macular degeneration who receive genetic testing for age-related macular degeneration, the evidence includes genetic association studies and risk-prediction models. Relevant outcomes are test accuracy, change in disease status, and functional outcomes. The clinical utility of genetic testing in patients who have age-related macular degeneration is limited, in that genetic testing has not been shown to be superior to clinical evaluation in determining the risk of progression of disease. In addition, there is no known association with specific genotypes and specific therapies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether use of genetic testing improves the net health outcome in patients with suspected age-related macular degeneration or disease progression in those with age-related macular degeneration.

Policy Statements

Genetic testing for macular degeneration is considered investigational.

Policy Guidelines

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It was implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Macular degeneration, the leading cause of severe vision loss in people older than age 60 years, occurs when the central portion of the retina (the macula) deteriorates. Because the disease develops as a person ages, it is often referred to as age-related macular degeneration. In 2019, approximately 19.8 million Americans 40 years of age and older were living with age-related macular degeneration.^1,Sex- and age-standardized rates of age-related macular degeneration were lower for non-Hispanic Black people (7.0%) than for other racial and ethnic groups (13.3%). 

There are 2 major types of age-related macular degeneration, known as the dry form and the wet form. The dry form is much more common, accounting for 85% to 90% of all cases of age-related macular degeneration, and it is characterized by the buildup of yellow deposits called drusen in the retina and slowly progressive vision loss. The condition typically affects vision in both eyes, although vision loss often occurs in 1 eye before the other. Age-related macular degeneration is generally thought to progress along a continuum from dry age-related macular degeneration to neovascular wet age-related macular degeneration, with approximately 10% to 15% of all age-related macular degeneration patients eventually developing the wet form. Occasionally patients with no prior signs of dry age-related macular degeneration present with wet age-related macular degeneration as the first manifestation of the condition.

The wet form of age-related macular degeneration, sometimes referred to as "vision-threatening" or "late stage" age-related macular degeneration, is characterized by the growth of abnormal blood vessels from the choroid underneath the macula and is associated with severe vision loss that can rapidly worsen. The abnormal vessels leak blood and fluid into the retina, which damages the macula, leading to permanent loss of central vision.

Major risk factors for age-related macular degeneration include older age, cigarette smoking, cardiovascular diseases, nutritional factors, and certain genetic markers. Age appears to be the most important risk factor because the chance of developing the condition increases significantly as a person gets older. Smoking is another established risk factor. Other factors that may increase the risk of age-related macular degeneration include high blood pressure, heart disease, a high-fat diet or a diet low in certain nutrients (eg, antioxidants, zinc), and obesity. Observational data (N=17,174) from the European EYE-RISK Consortium suggest that the odds of age-related macular degeneration increase by at least 2 times in patients with both genetic risk and predisposing lifestyle factors (eg, smoking and low dietary intake of vegetables, fruit, and fish).^2,

Clinical Diagnosis

Age-related macular degeneration can be detected by routine eye exams, with one of the most common early signs being the presence of drusen or pigment clumping. An Amsler Grid test, a pattern of straight lines that resembles a checkerboard, may also be used. In an individual with age-related macular degeneration, some of the straight lines may appear wavy or missing.

If age-related macular degeneration is suspected, fluorescein angiography and/or optical coherence tomography may be performed. Angiography involves injecting a dye into the bloodstream to identify leaking blood vessels in the macula. Optical coherence tomography captures a cross-sectional image of the macula and aids in identifying fluid beneath the retina and in documenting degrees of retinal thickening.

Treatment

There is currently no cure for macular degeneration, but certain treatments may prevent severe vision loss or slow disease progression. For dry age-related macular degeneration, there is no medical treatment; however, changing certain lifestyle risks may slow age-related macular degeneration onset and progression. The goal for wet (advanced) age-related macular degeneration is early detection and treatment aimed at preventing the formation of new blood vessels or sealing the leakage of fluid from blood vessels that have already formed. Treatment options include laser photocoagulation, photodynamic therapy, surgery, anti-angiogenic drugs, and combination treatments. Anti-angiogenesis drugs block the development of new blood vessels and leakage from the abnormal vessels within the eye that cause wet macular degeneration and may lead to patients regaining lost vision. The Age-Related Eye Disease Study (2001), a large study performed by the National Eye Institute of the National Institutes of Health, showed that, for certain individuals (those with extensive drusen or neovascular age-related macular degeneration in 1 eye), high doses of vitamins C, E, beta-carotene, and zinc may provide a modest protective effect against the progression of age-related macular degeneration.^3,

Genetic Testing

It has been reported that genetic variants associated with age-related macular degeneration account for approximately 70% of the risk for the condition.^4,

More than 25 genes have been reported to influence the risk of developing age-related macular degeneration, discovered initially through family-based linkage studies, and subsequently through large-scale genome-wide association studies. Genes influencing several biologic pathways, including genetic loci associated with the regulation of complement, lipid, angiogenic, and extracellular matrix pathways, have been found to be associated with the onset, progression, and bilateral involvement of early, intermediate, and advanced stages of age-related macular degeneration.^5,

Loci based on common single nucleotide variants contribute to the greatest risk of age-related macular degeneration:

• The long (q) arm of chromosome 10 in a region known as 10q26 contains 2 genes of interest, ARMS2 and HTRA1. Changes in both genes have been studied as possible risk factors for the disease; however, because the 2 genes are so close together, it is difficult to tell which is associated with age-related macular degeneration risk or whether increased risk results from variations in both genes.

• Common and rare variants in the complement factor H (CFH) gene.

Other confirmed genes in the complement pathway include C2, C3, CFB, and CFI.^5,

On the basis of large genome-wide association studies, high-density lipoprotein cholesterol pathway genes have been implicated, including CETP and LIPC, and possibly LPL and ABCA1.^5, The collagen matrix pathway genes COL10A1 and COL8A1, apolipoprotein E (APOE), and the extracellular matrix pathway genes, TIMP3 and FBN2, have also been linked to age-related macular degeneration. Genes involved in DNA repair (RAD51B) and in the angiogenesis pathway (VEGFA) have also been associated with age-related macular degeneration.

Commercially Available Testing for Age-Related Macular Degeneration

Commercially available genetic testing for age-related macular degeneration is aimed at identifying those individuals who are at risk of developing advanced age-related macular degeneration.

Arctic Medical Laboratories offers Macula Risk®, which uses patient clinical information and the patient’s genotype for 15 associated biomarkers in an algorithm to identify whites at high risk for progression of early or intermediate age-related macular degeneration to advanced forms of age-related macular degeneration. A Vita Risk® report is also provided with vitamin recommendations based on the CFH and ARMS2 genotype.

23andMe® includes testing for CFH, ARMS2, and C2.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Rationale

This evidence review was created in November 2013 and has been updated regularly with searches of the PubMed database. The most recent literature update was conducted through January 12, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Testing Asymptomatic Individuals with Risk of Developing Age-Related Macular Degeneration

Clinical Context and Test Purpose

The purpose of genetic testing in asymptomatic individuals with risk of developing age-related macular degeneration is to identify single nucleotide variants for primary prevention or earlier detection of disease for more timely intervention to affect course of disease progression.

The question addressed in this evidence review is: Does genetic testing improve the net health outcome in asymptomatic individuals with risk of developing age-related macular degeneration?

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is asymptomatic individuals with risk of developing age-related macular degeneration.

Interventions

The test being considered is genetic testing for age-related macular degeneration.

Comparators

The following practice is currently being used to make decisions about the risk of developing age-related macular degeneration: standard clinical management without genetic testing.

Outcomes

The general outcomes of interest are improvements in disease status and functional outcomes. Additional outcomes of interest are test accuracy and the initiation and frequency of monitoring for assessing changes in disease status.

Potential harmful outcomes would be those resulting from false-positive or false-negative test results. False-positive test results can lead to clinical management changes that may not be beneficial. False-negative test results can lead to absence of clinical management changes.

Study Selection Criteria

For the evaluation of clinical validity of genetic testing for macular degeneration, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores).

• Included a suitable reference standard.

• Patient/sample clinical characteristics were described.

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Current models for predicting age-related macular degeneration risk include various combinations of epidemiologic, clinical, and genetic factors, and give areas under the curve of approximately 0.8.^6,7, By plotting the true- and false-positives of a test, an area under the curve measures the discriminative ability of the test, with a perfect test giving an area under the curve of 1.^8,

An analysis by Seddon et al (2009) demonstrated that a clinical model of age-related macular degeneration risk, which included age, sex, education, baseline age-related macular degeneration grade, smoking, and body mass index, had an area under the curve of 0.757.^9, The addition of the genetic factors (single nucleotide variants) in CFH, ARMS2, C2, C3, and CFB increased the area under the curve to 0.821. In a later report, Seddon et al (2015) included 10 common and rare genetic variants in their risk-prediction model, resulting in an area under the curve of 0.911 for progression to advanced age-related macular degeneration.^10, The Age-Related Eye Disease Study (AREDS) Simple Scale, which rates the severity of age-related macular degeneration based on the presence of large drusen and pigment changes to predict the rate of advanced age-related macular degeneration, is considered to have the greatest predictive value.^6,11, Klein et al (2011) constructed a predictive model that included age, family history, smoking, the AREDS Simple Scale score, presence of very large drusen, presence of advanced age-related macular degeneration in one eye, and genetic factors (CFH, ARMS2). The area under the curve was 0.865 without genetic factors included and 0.872 with genetic factors included.^11, Govindaiah et al (2021) reported that a prediction model for development of age-related macular degeneration using AREDS data had an area under the curve of 0.69 using genetic data only, 0.77 using genetic and sociodemographic data, and 0.92 using genetic, sociodemographic, and retinal imaging data.^12, Ajana et al (2021) also reported an area under the curve at 5 years of 0.92 for an age-related macular degeneration model that included clinical, genetic, and lifestyle factors.^13, de Breuk et al (2021) and the EYE-RISK consortium found that patients with late age-related macular degeneration had significantly higher genotype assay risk scores than patients with early or intermediate disease (p<.001) or no disease (p<.001) based on a European case-control population (N=4740).^14,

Although these risk models suggest some small incremental increase in the ability to assess risk of developing advanced age-related macular degeneration based on genetic factors, the clinical validity is not established.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

What can be done for an individual whose genetic test indicates that they are at high risk for vision loss from age-related macular degeneration? The possible clinical utility of genetic testing for age-related macular degeneration can be divided into disease prevention, disease monitoring, and therapy guidance, as discussed below.

• Prevention: Genetic testing and risk prediction for age-related macular degeneration would have clinical utility if a preventive therapy involved an intervention that went beyond good health practices (eg, no smoking, balanced diet, exercise, nutrient supplements). If a preventive therapy existed, the optimal risk-benefit point along the age-related macular degeneration risk profile for every given age would need to be established so that it could be determined which individuals should receive those treatments and at what age to start the intervention. Currently, no preventive measures are available; high-dose antioxidants and zinc supplements have been shown to reduce disease progression.^3,

• Monitoring: If a patient is identified as high-risk, changes in the frequency of monitoring may occur and could include home monitoring devices or the use of technology such as preferential hyperacuity perimetry to detect early or subclinical wet age-related macular degeneration. However, the impact of more frequent monitoring for high-risk patients is not known.^6,

• Direction of therapy: No consistent associations between response to vitamin supplements and genetic variants have been established.^{15,16,17,18,19,}

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs). No such trials were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. A chain of evidence cannot be constructed.

Section Summary: Asymptomatic Individuals with Risk of Developing Age-Related Macular Degeneration

Evidence from studies has indicated that the clinical sensitivity of genetic testing for genes associated with age-related macular degeneration may have small incremental effects on assessing risk of developing age-related macular degeneration. Risk-prediction models incorporate factors such as age, sex, smoking, body mass index, and genetic factors. The true clinical specificity of genetic variants in age-related macular degeneration-related genes is uncertain because of the multifactorial nature of disease development and progression.

Direct evidence of the clinical utility of genetic testing in asymptomatic individuals at risk for developing age-related macular degeneration is lacking. While genetic variants have been used in risk-prediction models, no consistent associations between specific genetic variants and response to specific treatments have been established.

Summary of Evidence

For individuals who are asymptomatic with risk of developing age-related macular degeneration who receive genetic testing for age-related macular degeneration, the evidence includes genetic association studies and risk-prediction models. Relevant outcomes are test accuracy, change in disease status, and functional outcomes. The clinical validity of genetic testing appears to provide a small, incremental benefit to risk stratification based on nongenetic risk factors. The clinical utility of genetic testing for age-related macular degeneration is limited, in that there are currently no preventive measures that can be undertaken. No studies have shown improvements in health outcomes in patients identified as being at high-risk based on genetic testing. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2 

Testing Individuals with Age-Related Macular Degeneration

Clinical Context and Test Purpose

The purpose of genetic testing in patients who have age-related macular degeneration is to identify single nucleotide variants that potentially predict response to treatment.

The question addressed in this evidence review is: Does genetic testing for age-related macular degeneration improve the net health outcome in individuals with age-related macular degeneration?

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is symptomatic individuals with age-related macular degeneration.

Interventions

The test being considered is genetic testing to determine prognosis or predict response to therapy.

Comparators

The following practice is currently being used to make decisions about managing age-related macular degeneration: standard clinical management without genetic testing.

Outcomes

The general outcomes of interest are improvements in disease status and functional outcomes. Additional outcomes of interest are test accuracy and the initiation and frequency of monitoring for assessing changes in disease status and effects of management decisions on short-term and long-term functional outcomes.

Potential harmful outcomes are those resulting from false-positive or false-negative test results. False-positive test results can lead to clinical management changes that may not be beneficial. False-negative test results can lead to absence of clinical management changes.

Study Selection Criteria

For the evaluation of clinical validity of the genetic test for macular degeneration, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores).

• Included a suitable reference standard.

• Patient/sample clinical characteristics were described.

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Clinical validity is how the presence of specific single nucleotide variants provides accurate prognosis for disease course and predicts response to treatment. Evidence supporting the clinical validity of accurate disease prognosis and response to treatment was not identified.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

What can be done for an individual with age-related macular degeneration using genetic test results for prognosis and prediction of response to treatment? The possible clinical utility of genetic testing for age-related macular degeneration includes disease monitoring and therapy guidance, as discussed below.

• Monitoring: There is currently no cure for macular degeneration, but genetic variants may provide more accurate prognosis on disease progression. Frequency of monitoring may be increased if a genetic variant is associated with a more rapid or severe disease course.

• Direction of therapy: No consistent associations between response to vitamin supplements or anti-vascular endothelial growth factor therapy and VEGF gene variants have been established.^{15,16,17,18,19,20,}

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs. No such trials were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. A chain of evidence cannot be constructed.

Section Summary: Individuals with Age-Related Macular Degeneration

Direct evidence of the clinical utility of genetic testing in individuals with age-related macular degeneration is lacking. While genetic variants have been used in risk-prediction models, there have been no consistent associations between specific genetic variants and response to treatments.

Summary of Evidence

For individuals who have age-related macular degeneration who receive genetic testing for age-related macular degeneration, the evidence includes genetic association studies and risk-prediction models. Relevant outcomes are test accuracy, change in disease status, and functional outcomes. The clinical utility of genetic testing in patients who have age-related macular degeneration is limited, in that genetic testing has not been shown to be superior to clinical evaluation in determining the risk of progression of disease. In addition, there is no known association with specific genotypes and specific therapies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Ophthalmology

The 2014 American Academy of Ophthalmology (AAO) recommendations specific to genetic testing for complex eye disorders like age-related macular degeneration have indicated that the presence of any 1 of the disease-associated variants is not highly predictive of disease development.^21, The AAO found that, in many cases, standard clinical diagnostic methods like biomicroscopy, ophthalmoscopy, tonography, and perimetry would be more accurate for assessing a patient’s risk of vision loss from a complex disease than the assessment of a small number of genetic loci. The AAO concluded that genetic testing for complex diseases will become relevant to the routine practice of medicine when clinical trials demonstrate that patients with specific genotypes benefit from specific types of therapy or surveillance; until such benefit can be demonstrated, routine genetic testing of patients with complex eye diseases, or unaffected patients with a family history of such diseases, is not warranted.

In 2019, AAO published a Preferred Practice Pattern on age-related macular degeneration, which noted that the routine use of genetic testing is not recommended at this time due to lack of prospective clinical evidence.^22,

American Society of Retina Specialists

In 2017, the American Society of Retina Specialists published special correspondence on the use of genetic testing in the management of patients with age-related macular degeneration.^23, The Society concluded that:

• While age-related macular degeneration genetic testing may provide information on progression from intermediate to advanced age-related macular degeneration, there is no clinical evidence that altering management of patients with genetically higher risk for progression results in better visual outcomes compared with patients with genetically lower risk for progression.

• Age-related macular degeneration genetic testing in patients with neovascular age-related macular degeneration does not provide clinically relevant information regarding response to anti-vascular endothelial growth factor treatment and is therefore not recommended for this population.

• Currently, there is insufficient evidence to support the use of genetic testing in patients with age-related macular degeneration in regard to nutritional supplement recommendations.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT: national clinical trial.

References

1. Centers for Disease Control and Prevention (CDC). Prevalence of Age-Related Macular Degeneration (AMD). Updated October 31, 2022. https://www.cdc.gov/visionhealth/vehss/estimates/amd-prevalence.html#:~:text=Overall%20Findings&text=Prevalence%20of%20AMD%20increased%20with,among%20people%20aged%20%E2%89%A585. Accessed January 12, 2024.
2. Colijn JM, Meester-Smoor M, Verzijden T, et al. Genetic Risk, Lifestyle, and Age-Related Macular Degeneration in Europe: The EYE-RISK Consortium. Ophthalmology. Jul 2021; 128(7): 1039-1049. PMID 33253757
3. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. Oct 2001; 119(10): 1417-36. PMID 11594942
4. Gorin MB. Genetic insights into age-related macular degeneration: controversies addressing risk, causality, and therapeutics. Mol Aspects Med. Aug 2012; 33(4): 467-86. PMID 22561651
5. Lim LS, Mitchell P, Seddon JM, et al. Age-related macular degeneration. Lancet. May 05 2012; 379(9827): 1728-38. PMID 22559899
6. Kim IK. Genetic testing for AMD inches forward. 2012; https://www.reviewofophthalmology.com/article/genetic-testing-for-amd-inches-forward. Accessed January 12, 2024.
7. Hageman GS, Gehrs K, Lejnine S, et al. Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration. Hum Genomics. Jul 2011; 5(5): 420-40. PMID 21807600
8. Jakobsdottir J, Gorin MB, Conley YP, et al. Interpretation of genetic association studies: markers with replicated highly significant odds ratios may be poor classifiers. PLoS Genet. Feb 2009; 5(2): e1000337. PMID 19197355
9. Seddon JM, Reynolds R, Maller J, et al. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. May 2009; 50(5): 2044-53. PMID 19117936
10. Seddon JM, Silver RE, Kwong M, et al. Risk Prediction for Progression of Macular Degeneration: 10 Common and Rare Genetic Variants, Demographic, Environmental, and Macular Covariates. Invest Ophthalmol Vis Sci. Apr 2015; 56(4): 2192-202. PMID 25655794
11. Klein ML, Francis PJ, Ferris FL, et al. Risk assessment model for development of advanced age-related macular degeneration. Arch Ophthalmol. Dec 2011; 129(12): 1543-50. PMID 21825180
12. Govindaiah A, Baten A, Smith RT, et al. Optimized Prediction Models from Fundus Imaging and Genetics for Late Age-Related Macular Degeneration. J Pers Med. Nov 01 2021; 11(11). PMID 34834479
13. Ajana S, Cougnard-Grégoire A, Colijn JM, et al. Predicting Progression to Advanced Age-Related Macular Degeneration from Clinical, Genetic, and Lifestyle Factors Using Machine Learning. Ophthalmology. Apr 2021; 128(4): 587-597. PMID 32890546
14. de Breuk A, Acar IE, Kersten E, et al. Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium. Ophthalmology. Nov 2021; 128(11): 1604-1617. PMID 32717343
15. Fauser S, Lambrou GN. Genetic predictive biomarkers of anti-VEGF treatment response in patients with neovascular age-related macular degeneration. Surv Ophthalmol. 2015; 60(2): 138-52. PMID 25596882
16. Chew EY, Klein ML, Clemons TE, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology. Nov 2014; 121(11): 2173-80. PMID 24974817
17. Hagstrom SA, Ying GS, Maguire MG, et al. VEGFR2 Gene Polymorphisms and Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration. Ophthalmology. Aug 2015; 122(8): 1563-8. PMID 26028346
18. Hagstrom SA, Ying GS, Pauer GJ, et al. VEGFA and VEGFR2 gene polymorphisms and response to anti-vascular endothelial growth factor therapy: comparison of age-related macular degeneration treatments trials (CATT). JAMA Ophthalmol. May 2014; 132(5): 521-7. PMID 24652518
19. Awh CC, Lane AM, Hawken S, et al. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. Nov 2013; 120(11): 2317-23. PMID 23972322
20. Balikova I, Postelmans L, Pasteels B, et al. Genetic biomarkers in the VEGF pathway predicting response to anti-VEGF therapy in age-related macular degeneration. BMJ Open Ophthalmol. 2019; 4(1): e000273. PMID 31909188
21. Stone EM, Aldave AJ, Drack AV, et al. Recommendations of the American Academy of Ophthalmology Task Force on Genetic Testing. 2014; https://www.aao.org/clinical-statement/recommendations-genetic-testing-of- inherited-eye-d. Accessed January 12, 2024.
22. Flaxel CJ, Adelman RA, Vemulakonda GA, et al; American Academy of Ophthalmology Preferred Practice Pattern (PPP) Retina/Vitreous Committee. Age-Related Macular Degeneration PPP. 2019; https://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp. Accessed January 12, 2024.
23. Csaky KG SA, Kaiser PK, et al. The Use of Genetic Testing in the Management of Patients with Age-Related Macular Degeneration: American Society of Retina Specialists Genetics Task Force Special Report. 2017; https://www.asrs.org/content/documents/articleasrstaskforcereportjvrd117.pdf. Accessed January 12, 2024.

Codes

Policy History